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doi: https://doi.org/10.1101/2023.02.06.527335

Paradoxical activation of oncogenic signaling as a cancer treatment strategy.

Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M. Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Hendrik J. Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Chrysa Papagianni, Marcelo S. da Silva, Robin Jansen, Antonio Mulero-Sánchez, Elke Malzer, August Vidal, Cristina Santos, Ramón Salazar, Rosangela A. M. Wailemann, Thompson E. P. Torres, Giulia De Conti, Jonne A. Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S. Kovach, Hugo A. Armelin, Hein te Riele, Alexander van Oudenaarden, Haojie Jin, Roderick L. Beijersbergen, Alberto Villanueva, Rene H. Medema, Rene Bernards


Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

Competing Interest Statement

R.B., J.K. and M.H.D are listed as inventors of a patent describing the drug combinations discovered here. R.B. is a member of the board of directors of Lixte Biotechnology. R.B and M.H.D. are shareholders of Lixte Biotechnology. J.K. is employee of Lixte and shareholder in the company. This work was supported in part by a research grant for Lixte Biotechnology. A.V. and A.Vil. are co-founders of Xenopat S.L.